Transdermal delivery of estrogens and progestins for providing contraception is a known concept (Sitruk-Ware, Transdermal application of steroid hormones for contraception, 3 Steroid Biochem Molecul Biol, Volume 53, p 247-251). However, estrogens and progestins do generally poorly penetrate the skin, for which reason it is common, in transdermal systems, to incorporate agents with skin penetrating enhancing effect.
The following documents describe a number of transdermal systems with a progestin and an estrogen present in the adhesive layer and wherein the need of penetration enhancers is emphasised:
WO 92/07590 describes compositions with penetration enhancers for the transdermal delivery of Gestodene and an estrogen so as to achieve maximal plasma levels of Gestodene of about 0.9 ng/ml.
WO 97/397443 relates to a transdermal system containing between 30 to 60% of penetration enhancers so as to deliver a contraceptively effective amount of an estrogen and a progestin.
WO 01/37770 relates to transdermal systems containing between 10 to 60% of penetration enhancers for delivery of Ethinylestradiol and Levonorgestrel in contraceptively effective amounts.
U.S. Pat. No. 5,512,292 is directed to compositions comprising a contraceptively effective amount of Gestodene and an estrogen, such as Ethinylestradiol, together with a suitable permeation enhancer. The amount of the estrogen co-delivered is kept at a constant and contraceptive effective rate while the amount of Gestogen co-delivered varies depending on the phase of the menstrual cycle.
In U.S. Pat. No. 5,376,377 comparable studies between transdermal systems with and without penetration enhancers are shown. The studies include an adhesive layer made of ethylene vinyl acrylate and as the active ingredient, Gestodene and an estrogen (ethinylestradiol). The study results indicate the need of incorporation penetration enhancers in the adhesive layer so as to achieve contraceptive effective amounts. Maximal plasma levels of about 0.8 ng/ml were achieved.
Finally, WO 90/04397 also discloses examples of compositions for transdermal delivery of gestodene, optionally in combination with an estrogen, such as Ethinylestradiol, wherein the composition further may comprise a penetration enhancer, such as 1,2-propandiol or isopropylmyristat. As adhesive layer is mentioned a number of various polymers. Examples on polar polymers (polyacrylates and silicones) in combination with a penetration enhancer are specifically disclosed. The resulting plasma levels of Gestodene at steady state conditions were approx. 250 to 337 pg/ml.
In addition to penetration enhancers, it is also suggested to add solubilising agents or the like to the drug-containing layer in order to increase the amount of dissolved drug or to add agents inhibiting the crystallisation of the drug in the layer.
For example, in U.S. Pat. No. 6,521,250 is disclosed an adhesive layer that comprises a mixture of styrene-isoprene block copolymer and a hydrogenated resin acid or its derivatives, the amount of the resin being of 55-92%. Such an adhesive layer seems suitable for the transdermal delivery of estradiol in combination with a progestin in that such systems have a proper adhesive contact with the skin for long-term application and prevent crystallisation of the hormones.
U.S. Pat. No. 5,904,931 relates to TTS systems containing in the drug-containing layer a steroid (such as Gestodene) and dimethyl isosorbide. The latter enhances the solubility of the steroid in the drug-containing layer. The concentration of the Gestodene in the drug-containing layer may vary from 1-40% by weight of the layer and the drug-containing layer may consist of adhesives such as polyacrylates, silicones, styrene-butadiene co-polymers and polyisobutylenes. Especially, polar polymers, such as polyacrylates, are suitable.
DE 199 06 152 relates to a transdermal drug delivery system in which Gestodene is embedded in a polar polymer, such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, and hydroxypropylcellulose, previous to being added to an adhesive polymer, such as polyisobutylene. Thus, this transdermal drug delivery system is a twophase system and the drug-containing layer is not transparent because of the content of the polar polymers, which upon exposure to water will result in the presence of milky-white spots. The amount of Gestodene in the drug-containing layer is 5.1% by weight of the drug-containing layer.
In WO 02/45701 it is emphasised that the addition of a rosin ester in an amount up to 25% by weight to an adhesive layer may sufficiently suppress crystal formation of active agents such as for example hormones. The adhesive layer may include all non-toxic natural and synthetic polymers known and which are suitable for use in transdermal systems, for example polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers and the like. Particularly, polyacrylates are emphasised. The TTS system is suitable for steroids (Gestodene), which may be incorporated in the adhesive layer in an amount substantially at or near or even above the saturation with respect to their concentration in the carrier composition rather than substantially at subsaturation. Preferably, the amount of the steroid is from about 0.1% to about 6% by weight, based on the dry weight of the total carrier composition.
Unfortunately, penetration enhancers may adversely affect the skin such as irritating the skin, which to some extend renders transdermal systems unacceptable for the user. Additionally, it is generally known that penetration enhancers may negatively affect the stability of active substances rendering long-term storage problematic. Furthermore, it is also recognised that the viscosity is reduced by incorporation of penetration enhancers resulting in the risk of formation of dark rings along the edges of the patch.
Therefore, there is a need for transdermal systems without the above-mentioned. drawbacks, such as transdermal systems that do not require penetration enhancers for achieving therapeutically effective amounts of a steroidal hormone, such as Gestodene.
Gestodene is a known orally active synthetic progestin with a progesterone-like profile of activity (see, U.S. Pat. No. 4,081,537). It is used as an oral contraceptive in combination with certain estrogens.